Immunological Targeting of Pathological Tau Proteins

Abstract

The present invention relates to methods and compositions for treating, preventing, and diagnosing Alzheimer's Disease or other tauopathies in a subject by administering an immunogenic tau peptide or an antibody recognizing the immunogenic tau epitope under conditions effective to treat, prevent, or diagnose Alzheimer's Disease or other tauopathies. Also disclosed are methods of promoting clearance of aggregates from the brain of the subject and of slowing progression of tau-pathology related behavioral phenotype in a subject.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 (A) an antibody, or binding portion thereof, having an antigenic specificity for an isolated Tau peptide whose amino acid sequence consists of:
 (a) the amino acid sequence of SEQ ID NO:57; 
 (b) an amino acid sequence selected from the group consisting of SEQ ID NO:13 and SEQ ID NO:42; 
 (c) an amino acid sequence selected from the group consisting of SEQ ID NO:74 and SEQ ID NO:99; 
 (d) an amino acid sequence selected from the group consisting of SEQ ID NO:5 and SEQ ID NO:34; 
 (e) an amino acid sequence selected from the group consisting of SEQ ID NO:23 and SEQ ID NO:52; and 
 (f) an amino acid sequence selected from the group consisting of SEQ ID NO:100-103; and 
 and 
   (B) a pharmaceutically-acceptable carrier, diluent or stabilizer;   wherein said composition comprises an amount of said antibody, or binding portion thereof, sufficient to treat Alzheimer's disease or other tauopathy in a recipient subject or to reduce the severity of Alzheimer's disease or said other tauopathy in said recipient subject.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein said antibody, or binding portion thereof, has an antigenic specificity for an isolated Tau peptide whose amino acid sequence consists of the amino acid sequence of SEQ ID NOs:5, 13, 23 or 99. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein said antibody, or binding portion thereof, has an antigenic specificity for an isolated Tau peptide whose amino acid sequence consists of the amino acid sequence of SEQ ID NOs:34, 42, 52, 57 or 74. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein said antibody, or binding portion thereof, has an antigenic specificity for an isolated Tau peptide whose amino acid sequence consists of the amino acid sequence of SEQ ID NOs:100-103. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein said composition additionally comprises one or more additional antibodies, or binding portions thereof, having an antigenic specificity for a peptide having an amino acid sequence selected from the group consisting of SEQ ID NOs:81-100. 
     
     
         6 . The pharmaceutical composition of  claim 4 , wherein said composition additionally comprises one or more additional antibodies, or binding portions thereof, having an antigenic specificity for a peptide having an amino acid sequence selected from the group consisting of SEQ ID NOs:81-100. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein said composition additionally comprises one or more additional antibodies, or binding portions thereof, having an antigenic specificity for one or more different amyloidogenic proteins or peptides selected from the group consisting of an amyloid-beta protein precursor, a prion protein, α-synuclein, amyloid-β, an islet amyloid polypeptide, apolipoprotein AI, apolipoprotein AII, lyzozyme, cystatin C, gelsolin, atrial natriuretic factor, calcitonin, keratoepithelin, lactoferrin, an immunoglobulin light chain, transthyretin, A amyloidosis, β2-microglobulin, an immunoglobulin heavy chain, a fibrinogen alpha chain, prolactin, keratin, and medin. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein said tauopathy is selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, dementia pugilistica, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallerworden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atrophy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-guanamian motor neuron disease with neurofibrillary tangles, chronic traumatic encephalopathy, and postencephalitic parkinsonism. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein said composition promotes the reduction or clearance of Tau aggregates from the brain of said recipient subject, or reduces the severity of the formation of Tau aggregates in said recipient subject. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said Tau aggregates are neurofibrillary tangles or their pathological Tau precursors. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein said composition slows progression of Tau pathology-related cognitive impairment in said recipient subject, or reduces the severity of said progression. 
     
     
         12 . A pharmaceutical composition comprising:
 (I) an antibody, or binding portion thereof, having an antigenic specificity for an isolated Tau peptide whose amino acid sequence consists of the amino acid sequence of SEQ ID NO:82;
 and 
   (II) one or more additional antibodies, or binding portions thereof, having an antigenic specificity to a peptide having an amino acid sequence selected from the group consisting of SEQ ID NOs:81-100;   and   (III) a pharmaceutically-acceptable carrier, diluent or stabilizer   wherein said composition comprises an amount of said antibody, or binding portion thereof, sufficient to treat Alzheimer's disease or other tauopathy in a recipient subject or to reduce the severity of Alzheimer's disease or said other tauopathy in said recipient subject.   
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein said composition additionally comprises one or more additional antibodies, or binding portions thereof, having an antigenic specificity for one or more different amyloidogenic proteins or peptides selected from the group consisting of an amyloid-beta protein precursor, a prion protein, α-synuclein, amyloid-β, an islet amyloid polypeptide, apolipoprotein AI, apolipoprotein AII, lyzozyme, cystatin C, gelsolin, atrial natriuretic factor, calcitonin, keratoepithelin, lactoferrin, an immunoglobulin light chain, transthyretin, A amyloidosis, β2-microglobulin, an immunoglobulin heavy chain, a fibrinogen alpha chain, prolactin, keratin, and medin. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein said tauopathy is selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, dementia pugilistica, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallerworden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atrophy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-guanamian motor neuron disease with neurofibrillary tangles, chronic traumatic encephalopathy, and postencephalitic parkinsonism. 
     
     
         15 . The pharmaceutical composition of  claim 12 , wherein said composition promotes the reduction or clearance of Tau aggregates from the brain of said recipient subject, or reduces the severity of the formation of Tau aggregates in said recipient subject. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein said Tau aggregates are neurofibrillary tangles or their pathological Tau precursors. 
     
     
         17 . The pharmaceutical composition of  claim 12 , wherein said composition slows progression of Tau pathology-related cognitive impairment in said recipient subject, or reduces the severity of said progression.